Ninety-eight individuals were tested for VHL mutations--23 symptomatic and 75 asymptomatic individuals belonging to 16 families. Seven of the families had definite clinical criteria of VHL disease, five had sporadic hemangioblastoma, and four had CNS hemangioblastoma combined with minor visceral signs. Molecular genetic testing identified five germline mutations in six of the definite VHL families (sensitivity 85%), but none in the possible VHL and sporadic hemangioblastoma cases; four of these mutations had been previously described and one is a novel mutation present in two unrelated families. After patients carrying the mutation were identified, they underwent clinical screening and asymptomatic VHL-related lesions were identified in 43%.
Patients presenting with cerebellar hemangioblastomas at the Mexican National institute of Neurology and Neurosurgery to were prospectively enrolled alongside family members, resulting in 84 patients in 7 families with VHL mutations, and subjected to peripheral blood draw and PCR-based mutation screening, as well as full clinical screening for symptomatic individuals. One indiviudal presented with a c.362A>G mutation leading to a p.Asp121Gly missense change. This individual presented at 29Y with 2 cerebellar hemangioblastomas, bilateral retinal angioma, pancreatic cysts, kidney cysts, renal cell carcinoma, pheochromocytoma, and broad ligament cystadenoma. The family history of this patient is negative for the disease; one possibility is that she carries a de novo mutation, although the possibility of non-paternity could not be ruled out. Other affected individuals in Family D died at an early age. They were previously published in PMID: 20064270. ACMG Evidence Codes: 'PP2' because it is a missense variant in a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease.